Retro-prospective Observational Study on Risk of Progression in CP-CML Patients Eligible for TKI Discontinuation

• Conditions: Chronic Myeloid Leukemia

• Registration Number: NCT04621851
• Lead Sponsor: University of Milano Bicocca

Brief Summary

The purpose of this study is to investigate the safety profile of TKI discontinuation in clinical practice, with particular regard on the risk of progression after treatment discontinuation.

Detailed Description

This study will enroll approximately 3000 CP-CML patients that must have a history of at least 4 years of TKI treatment and at least 18 months of DMR. Events developing in patients after the end of discontinuation and TKI resumption will be considered as linked to the discontinuation if they will develop within 36 months from the end of discontinuation. This rule will apply also to subsequent TD attempts. In case of a second or subsequent discontinuation attempt after the failure of a previous one (for molecular relapse), patients must have re-achieved a DMR with TKI therapy resumption and must keep DMR for at least 18 months before another TD.

Collection of data will be retrospective and prospective, as each center will collect the data for 24 months. Patients who discontinued before the opening of this study will contribute to the retrospective cohort, while those who will discontinue after it will contribute to the prospective cohort. Patients who discontinued before the opening of this study but will continue their discontinuation after it, will contribute to both cohorts. For patients prospectively recruited, monitoring of disease status will be performed to assess the maintenance of the molecular remission during the study period.

Patients with an atypical BCR-ABL1 fusion gene, which does not allow the use of Q-RT-PCR, will be monitored by qualitative PCR and will be analyzed separately. For these patients, negativity of nested qualitative RT-PCR will be considered a surrogate of DMR of patients monitored by Q-RT-PCR, while loss of negativity of first-round qualitative PCR will be considered a surrogate of loss of MMR (i.e. molecular relapse). Accordingly, for patients monitored by qualitative PCR, TKI resumption after TD will be provided in case of a new positivity of first-round PCR.

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Study Timeline

• Study First Submitted: 2020-09-14
• Study Start: 2020-09-30
• Study First Submitted QC: 2020-11-03
• Study First Posted: 2020-11-09
• Primary Completion: 2021-09-30
• Status Verified: 2022-07
• Last Update Submitted: 2022-07-25
• Last Update Posted: 2022-07-26
• Study Completion: 2023-09-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 3000

Inclusion Criteria

1. Signed and dated IRB/IEC-approved informed consent for the prospective cohort patients.
2. Age >= 18 years.
3. Male or female patients with CML diagnosed in chronic phase (CP).
4. At least 4 years of TKI treatment.
5. At least 18 months of DMR.

Exclusion Criteria

• Allogeneic hematopoietic stem cell transplantation.
• CML diagnosed in AP or BC

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
The quantification of the risk of progression	36 Month	To quantify the risk of progression to accelerated phase (AP) or blast phase (BP), expressed as time adjusted rate (TAR), after TKI discontinuation in CML patients who undergo a first or subsequent TKI discontinuation attempt

Secondary Outcome Measures

Name	Time	Method
To compare the time adjusted rate (TAR) of progression from Chronic phase-Chronic Myeloid Leukemia to Accelerated phase (AP) or Blastic phase (BP) by using the percentage of blasts, promyelocytes, basophils or platelet in blood or bone marrow	36 Month	To compare the TAR (time adjusted rate) of progression to AP or BP that is obtained in the target population to that obtained in a similar population of patients with the same characteristics who do not discontinue TKI treatment
Rate of molecular relapse (loss of MR3 or MMR)	36 Month	Rate of molecular relapse (loss of MR3 or MMR) at 12 and 24 months after TKI discontinuation.
Progression free survival (PFS) after TKI discontinuation.	36 Month	PFS will be defined as time between discontinuation and progression to AP or BP.
Relapse free survival (RFS) after TKI discontinuation.	36 Month	Relapse free survival (RFS) after TKI discontinuation. RFS will be defined as time between discontinuation and loss of MMR (i.e. molecular relapse).
Percentage of relapsed patients who obtain a new deep molecular response (DMR) within 6-12 months of treatment resumption among all patients who restart TKI treatment because of a molecular relapse after TKI discontinuation.	36 Month	The following criteria will be used to define DMR (43): * MR4 = either (i) detectable disease with \<0.01% BCR-ABL1IS or (ii) undetectable disease in cDNA with \>10 000 ABL1 transcripts.; * MR4.5 = either (i) detectable disease with \<0.0032% BCR-ABL1IS or (ii) undetectable disease in cDNA with \>32 000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1.; * MR5 = either (i) detectable disease with \<0.001% BCR-ABL1IS or (ii) undetectable disease in cDNA with \>100 000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1.

Trial Locations

Locations (26)

CTMO Ematologia Ospedale "Businco"; 🇮🇹 Cagliari, Italy

McGill University - Jewish General Hospital Division of Hematology and Department of Oncology; 🇨🇦 Montréal, Quebec, Canada

University of Mannheim, Mannheim, Germania; 🇩🇪 Mannheim, Germany

Charité University of Berlin - Clinic of Medicine - Hematology and Oncology; 🇩🇪 Berlin, Germany

ASST-Monza; 🇮🇹 Monza, Italy/MB, Italy

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC di Ematologia; 🇮🇹 Milano, Italy/Milano, Italy

UO Ematologia O spedale Milano S. Raffaele; 🇮🇹 Miano, Italy

Istituto di Ematologia "Lorenzo e A. Seragnoli" Policlinico S. Orsola Malpighi,; 🇮🇹 Bologna, Italy

Universita di Tor Vergata Ospedale S. Eugenio; 🇮🇹 Rome, Italy/Rome, Italy

SOC Ematologia Az. Ospedaliera Pugliese Ciaccio (AOPC); 🇮🇹 Catanzaro, Italy

Università di Catania Cattedra di Ematologia Ospedale "Ferrarotto"; 🇮🇹 Catania, Italy

Ematologia Ospedale Cuneo; 🇮🇹 Cuneo, Italy

Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli"; 🇮🇹 Napoli, Italy

Unità operativa Ematologia e CTMO Az Ospedaliera Universitaria; 🇮🇹 Parma, Italy

Università di Pisa Azienda Ospedaliera Pisana Divisione di Ematologia; 🇮🇹 Pisa, Italy

Azienda Ospedaliera Universitaria Università degli Studi di Napoli "Federico II" Facoltà di Medicina e Chirurgia; 🇮🇹 Napoli, Italy

U.O. di Ematologia con trapianto A.U. Policlinico "Paolo Giaccone"; 🇮🇹 Palermo, Italy

Fondazione IRCCS Policlinico San Matteo; 🇮🇹 Pavia, Italy

Azienda Unità Sanitaria Locale IRCCS; 🇮🇹 Reggio Emilia, Italy

Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino S. G.Battista; 🇮🇹 Torino, Italy

Struttura Complessa a Dir. Universitaria Ematologia e Terapie Cellulari A.S.O. Ordine Mauriziano, P.O. U mberto I; 🇮🇹 Torino, Italy

U.O. di Ematologia Ospedale dell'Angelo Mestre; 🇮🇹 Venezia, Italy

U.O. Complessa di Ematologia Azienda ULSS 8 "Berica" Ospedale San Bortolo; 🇮🇹 Vicenza, Italy

University Hospital Clínic de Barcelona; 🇪🇸 Barcelona, Spain

S.C. Ematologia, Ospedale di Circolo e Fondazione Macchi Varese, ASST dei Sette Laghi,; 🇮🇹 Varese, Italy

Istituti Ospitalieri di Verona Div. di Ematologia Policlinico G.B. Rossi; 🇮🇹 Verona, Italy